Project Summary Neurodegeneration, which underlies the progression of Multiple Sclerosis (MS), is poorly reflected by standard clinical and radiological metrics. Brain volume, the most widely used MRI marker for neurodegeneration, measures only irreversible neuronal loss (atrophy). Complementary markers for monitoring the earlier stages of the neurodegeneration process are therefore needed, in order to better predict disease progression and assess the efficacy of treatment with neuroprotective agents. By satisfying a number of biomarker requirements, N-acetyl-aspartate (NAA), a metabolite quantified by proton MR spectroscopy (1H MRS), has the potential to fulfil this role. Unsatisfactory reproducibility and sensitivity, however, have hampered its transition to clinical use. The goal of this work is to address these shortcomings by introducing a robust multiparametric NAA biomarker for neurodegeneration in early-stage MS. Using MRS Fingerprinting (MRSF), a novel method which represents a departure from conventional 1H MRS (cMRS), we will assess neurodegeneration by: (i) more accurate estimates of NAA concentrations, compared to those from cMRS; (ii) measurements of the neuronal microenvironment, in the form of NAA?s T1 and T2 relaxation times. Unlike cMRS, MRSF produces relaxation times (T1, T2) and transmitter inhomogeneity (B1+) per subject for NAA and water. These variables were previously not collected, due to prohibitively long protocols, forcing cMRS studies into using average values from patient cohorts evaluated in other studies, or more commonly, into assuming unchanged values across all subjects and all brain regions. Our group and others, however, have shown that relaxation times of water and metabolites in normal-appearing MS tissue are not only different from control values, but also exhibit regional and inter-subject variations. We therefore hypothesize that by accounting for these factors, and by integrating the relaxation times into a multiparametric classifier, MRSF will provide superior sensitivity compared to cMRS in measuring neurodegeneration. The hypothesis will be tested for recently-diagnosed patients with a relapsing-remitting course, in normal-appearing white matter, as well as in the thalamus, a region recently shown to be sensitive to early neurodegeneration in MS.